Flow cell, method for separating carrier-free radionuclides, and the radiochemical reaction thereof

ABSTRACT

The invention relates to a flow cell, a method for separating carrier-free radionuclides from a liquid or liquefiable target material, and the radiochemical reaction thereof. According to prior art, flow cells are known which require reaction volumes corresponding to the volume of the target material in order to carry out the desired reactions. The inventive flow cell ( 1 ) and method enable the reaction volume, and thus the quantity of starting material, to be reduced by a multiple by reducing the cylinder volume (=reaction volume). As the radioactively marked product is present in very small quantities (picomole to nanomole), the HPL-chromatographic separation of the non-reacted starting material is significantly improved. The economic efficiency of the method is increased due to the fact that small quantities of starting material can be used.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the US national phase of PCT applicationPCT/DE03/00332, filed 6 Feb. 2003, published 4 Sep. 2003 as WO03/073437, and claiming the priority of German patent application10208668.0 itself filed 28 Feb. 2002.

FIELD OF THE INVENTION

The invention relates to a flow cell as well as to a method ofseparating carrier-free radionuclides from liquids or liquefiable targetmaterial and their radiochemical reactions.

BACKGROUND OF THE INVENTION

Radionuclides can be made by nuclear conversion processes in acyclotron, for example by reirradiating a suitable target with protons.An exact description of a method of separating carrier-freeradionuclides from a target liquid is known, for example, from Germanpatent DE 195 00 428.

From German patent document DE 195 00 428 a device is also known (a flowcell) for the separation of carrier-free radionuclides from a targetliquid, which is comprised substantially of a cylinder of a carbon glass(Sigradur®) and an axial platinum cannula through which a cylindricalvessel can be filled or emptied through which the inert gas can be fedinto the chamber. The system is fixed by means of a plastic support andis sealed. At the lower end a flat funnel is worked which opens into theduct carrying off the water. In the head of the support, there is a gasfeed line as well as an opening through which the gas can be discharge.The cylinder of carbon glass (Sigradur®) and the platinum cannula areconnected to a direct current source and can be switched to serve eitheras the cathode or anode. For the recovery of the desired radionuclide,for example, (¹⁸F) fluoride from (¹⁸O)H₂O, the flow cell is filled with(¹⁸F) fluoride containing target water. The (¹⁸F) fluoride is indirectlydeposited on the surface of the cylinder and the (¹⁸O) water istransported out of the latter. The height of the zone at which the (¹⁸F)fluoride is indirectly fixed is identical with the level of the (¹⁸O)water in the cell.

In order that the radio isotope fixed on the surface can be completelytransferred to another liquid phase by reversal of the polarity of theelectric filled, it is necessary to match the level in the cell to whichthe latter was filled with the (¹⁸O) water. For the subsequent (¹⁸F)fluoridation, therefore, a reaction volume must be provided whichcorresponds to that of the target water. Thus it is necessary to matchthe quantity of the educt so that it corresponds at the optimal eductconcentration to this volume (for example 1.3 ml). Because of the verysmall quantities or proportions of these products (picomoles tonanomoles) with respect to the proportion of unoriented educt (μmol),difficulties in separation occur during purification and especiallyduring chromatographic purefaction. Since the mass of the eductsignificantly exceed the mass of the product, an HPL-chromatographicseparation can only run with poor resolution.

OBJECT OF THE INVENTION

It is thus an object of the invention to provide a device and a methodwhereby the reaction volume can be reduced. It is a further object ofthe invention to reduce the amount of material of the educt by amultiple while maintaining the optimum educt concentration.

SUMMARY OF THE INVENTION

The objects are attained according to the invention in that there is agap between the cylinder and the piston.

With the flow cell according to the invention and the method, it ispossible directly to reduce the cylinder volume (=reaction volume) andthereby reduce the quantity of the educt also by a multiple. Thereduction of the quantity of the educt simplifies the chromatographicpurification and enables a quantitative separation of the carrier-poormarker compound (product) from the educt. Since the reduced eductquantities can be used, the costs are reduced and the economy of themethod enhanced.

BRIEF DESCRIPTION OF THE DRAWING

The drawing shows an embodiment of the method and the device accordingto the invention by way of example. In the drawing:

FIG. 1 is a cross section through the flow cell in an end position I;

FIG. 2 is a cross section through the flow cell in an opposite endposition II; and

FIG. 3 is cross section taken along line A—A of FIG. 2.

SPECIFIC DESCRIPTION

FIG. 1 shows the flow cell 1 with a cylinder 2 receiving a cannula 3which is bounded from below by a piston 4 with a bore 5 connected by ayoke 6 with a cannula holder 7. The cylinder 2 can be filled with liquidor inert gas through the cannula 3. The flow cell 1 is fixed by asupport 8 and sealed. In the head part of the support 8, there are twofeed lines 9 and 10 through which the gases can be fed to the device orcarried away. In the head of the piston 11, there is a flat funnel 12which opens into a bore 5. The cylinder 2 and the cannula 3 areconnected to a direct current source 13 and can be selectively switchedfor use as the cathode or anode. In position I, the cannula 3 is locatedat the lower end of the cylinder 2. The piston 4 is located outside thecylinder 2. In the lower region 17 of the cylinder 2, two sealing rings15 and 16 seal the piston 4 with respect to the cylinder 2.

In FIG. 2 the same features of the device have been represented by thesame reference numerals. FIG. 2 shows the arrangement of the componentsof the flow cell 1 in Position II, with the piston 4 shifted into thecylinder 2. The cannula 3 is pushed out of the cylinder 2 by the amountto which the piston 4 projects into the cylinder 2. Between the piston 4and the cylinder 2, an annular gap 14 is formed. In FIG. 2 at the lowerportion of the cylinder, a section plane has been marked by thereference character “A”.

FIG. 3 shows the flow cell 1 in position II in a section along thesection plane A. The annular gap 14 can be seen between the piston 4 andthe cylinder 2.

The invention is described by way of example below.

At the beginning of the reaction the components of the flow cell 1 arearranged, for example, as follows (see also FIG. 1; Position I); thelower opening of the cannula 3, which is preferably made from platinumis located at the lower end 17 of the cylinder 2 and the piston 4 islocated externally of the cylinder 2. The flow cell 1 is filled throughthe bore 5 or the duct 3 with the (¹⁸F) fluoride containing targetwater, whereby the (¹⁸F) fluoride is anodically deposited on the surfaceof the cylinder 2 to which a DC voltage of, for example, 20 volts isapplied via the DC voltage source 13. The cannula 3 here serves as thecathode. The cylinder 2 is made in an advantageous embodiment of thedevice of a pore-free inert material, like for example carbon glass(Sigradur®), a noble metal or platinum.

The piston 4 should preferably be made from an inert material. Assuitable material, for example PEEK (polyetheretherketon), quartz glassor implement glass have been found to be suitable. It is, however, alsopossible to use a piston of an electrically conductive material whichcan then also be used as an electrode. The gap width or the differencein radius between the cylinder 2 and the piston 4 is dependent upon thefabrication method. Preferred is a radius difference between thecylinder 2 and the piston 4 of 0.4 mm. Suitable however also are gapwidths of <0.2 mm. For the ratio of the radii between the cylinder (r₁)and the piston (r₂), the following equations can apply:F ₁ =r ₁ ²*Π where F ₁=the area of the cylinder 2F ₂ =r ₂ ²*Π where F ₂=the area of the piston 4F ₃ =F ₁ −F ₂=Π(r ₁ ² −r ₂ ²) where F ₃=the area of the gap 14V ₃ =r ₁ ² −r ₂ ²=(r ₁ +r ₂)(r ₁ −r ₂)

-   -   where V₃=the volume of the gap 14        V ₁ /V ₃ =r ₁ ² /r ₁ ² −r ₂ ² =r ₁ ²/(r ₁ +r ₂)(r ₁ −r ₂)    -   where V₁=the volume of the cylinders 2

After the filling of the flow cell with the target solution (for example¹⁸O water), the radio isotope (for example ¹⁸F fluoride) is deposited onthe inner surface of the cylinder 2 and the ¹⁸O water is transported outof the flow cell 1 through the bore 5 in the piston 4. The height of thezone in which the (¹⁸F) fluoride is anodically fixed, corresponds to thefill level of the ¹⁸O water in the cylinder 2. The (¹⁸F) fluoride fixedon the surface of the cylinder 2 is then completely dissolved in anotherliquid phase like for example an organic phase transfer catalystcontaining solution ((K⊂2.2.2)₂C₂O₄ in dimethylsulfoxide=DMSO) byreversal of the electrical field. For that purpose it is necessary thatthe fill level of this liquid phase in the cylinder 2 match the fillingstate of the ¹⁸O water which was previously set. To avoid the need for areaction volume corresponding in amount to the target water volume forthe subsequent nucleophilic (¹⁸F) fluoridation, a displacement effect ofthe piston 4 is used. The piston 4 is shifted upwardly by a movement ofthe yoke 6 in this direction. Simultaneously the cannula 3 is shifted inthe cylinder 2 corresponding to the height of the piston 4 out of thecylinder 2. The volume that thus must be introduced into the cylinder 2must correspond to the volume of the gap 14 that is formed when thepiston 4 projects into the cell 1 (see FIG. 2, Position II) such thatthe upper end of the piston 4 coincides with the fill level which hasbeen determined by the (¹⁸F) fluoride fixed on the surface of thecylinder 2. In an advantageous configuration of the device, the ratio ofthe volume (V₁) of the cylinder 2 to the volume (V₃) of the gap amountsto 4:1 to 10:1. In an especially preferred configuration of the device,it amounts to 4:1. With an ¹⁸O water volume of, for example 1.3 ml, thevolume of the gap 14 at a fill level can amount to about 0.29 ml. Whenthe piston is shifted upwardly sufficiently that the upper end of thepiston 4 coincides with the fill level determined by the (¹⁸F) fluoridefixed on the surface of the cylinder (see FIG. 2, piston B), the (¹⁸F)fluoride can be transferred to the reaction solution by applying anelectric belt (with the (Sigradur® as the cathode). In this position,only the gap volume 14 is filled. The solution is sealed at the lowerend by two annular cylinders 15 and 16 (for example O-rings) withrespect to the piston 4 so that a lateral outflow of liquid from thelower end of the cylinder is prevented.

For emptying the reaction vessel, the vessel 4 is again lowered and theliquid transported outwardly through the cannula 3 or the bore 5 of thepiston 4.

In an advantageous configuration of the device and the method, the feedor the evacuation of the (¹⁸F) fluoride-containing target water and theorganic solvent are effected through different conduits. When, forexample, the supply of the (¹⁸F) fluoride-containing target water iseffected through the conduit 3, the transport of the organic solventwhich is used for desorption of the product is effected through the bore5 to avoid a contamination of the conduit 3. Thus a high effort cleaningof the conduit for the target water can be avoided. The transport of thetarget water will be self-understood to be possible also through thebore 5 and the transport of the organic solvent correspondingly throughthe conduit 3. It is important for a device which can be easilymanipulated and the method that a separate conduit is provided for eachof the different liquids.

Through the method of the invention and the device it is possible toreduce the edict quantity. This reduction in the mass of the educt isespecially advantageous for the subsequent chromatographic separation ofthe carrier-poor ¹⁸F-labeled product from the educt. In previously knownmethods and with previously known devices for the separation of thecarrier-free radionuclide and its radiochemical reaction, the eductquantity is significantly greater. Through the method and deviceaccording to the invention, the volume of the educt solution and thusthe quantity of the educt is reduced by a multiple (at least 3 to 4times) so that the chromatographic separation of educt and the¹⁸F-labeled product is significantly improved.

The reduction of the absolute educt quantity thus gives rise to a costsaving and therewith an improvement in the economy of the method.

EXAMPLE ¹⁸F-Leveling of N-Methylbenperidol

The (¹⁸F) fluoride-containing ¹⁸O water (1.3 ml) coming from the targetof the cyclotron is transported into the flow cell 1 through the bore 5of the piston 4. Upon application of an electrical voltage of 20 voltsfrom a direct current source 13 (anode=cylinder (2) of carbon glass),the carrier-poor radio isotope is identically adsorbed within about 8minutes on the surface of the cylinder 2. The ¹⁸O water is driven outthrough the bore 5 by means of helium. To dry the cylinder wall, theflow cell is filled once or twice each with 1.6 ml of water-freedimethylsul-oxide (DMSO) and emptied through the cannula 3 serving asthe counterelectrode. Through the cannula 3, a solution of 5 mg Kryptat([K⊂2.2.2]₂CO₃ in 300 μl DMSO) is introduced into the flow cell 1 andpiston 4 shifted by a motor so that the liquid surface reaches the upperboundary of the anodically deposited ¹⁸F fluoride. The potential isreversed (−2V) and the cylinder is heated for 5 minutes to 100° C. Afterdepolarization of the flow cell, the piston is brought into its lowerposition and through the cannula 3 of a solution of 2 mg ofN-methyl-desfluor-nitro-benperidol in 150 μl of DMSO is supplied. Thepiston 4 is shifted again into the upper position and the flow cell isheated for 10 minutes to 150° C. Then the flow cell is cooled withcompressed air to ambient temperature. The flow cell is emptied throughthe cannula 3, is washed with about 0.8 ml acetonitrile at 50° C. andthis solution is mixed with the DMSO product solution by a subsequentHPL-chromatography, the radiotracer (¹⁸F) N-methylbenperidol is purifiedand isolated.

1. A flow cell for separating carrier-free radionuclides from liquid orliquefiable target material and its radiochemical reaction, the flowcell comprising a cylinder extending along and centered on an axis andhaving upper and lower ends; a cannula extending axially in the cylinderfrom one of the cylinder ends and having a cannula end in the cylinder;a piston extending axially in the cylinder from the other of thecylinder ends and having a piston end spacedly juxtaposed with thecannula end, the piston having an outer surface separated from an innersurface of the cylinder by a gap between cylinder and the piston, avolume ratio between the cylinder and the gap being equal to between 4.1and 10.1; and supply means for applying a voltage differential betweenthe inner surface of the cylinder and the cannula.
 2. The flow cellaccording to claim 1 wherein a diameter of the piston is smaller than aninside diameter of the cylinder.
 3. The flow cell according to claim 1wherein the piston is comprised of chemically inert material.
 4. Theflow cell according to claim 1 wherein the piston is composed of PEEK,implement glass or quartz glass.
 5. The flow cell according to claim 1wherein the piston has a bore, the cell further comprising means forfeeding a fluid through the bore.
 6. The flow cell according to claim 1wherein the piston has a central bore, the cell further comprising meansfor feeding a fluid through the bore.
 7. The flow cell according toclaim 1 wherein the cylinder has a pore-free inert surface.
 8. The flowcell according to claim 1 wherein the cylinder is composed of chemicallyinert material.
 9. The flow cell according to claim 1 wherein thecylinder is composed of carbon glass, a noble metal or platinum.
 10. Theflow cell according to claim 1 wherein the inner surface of the cylinderis electrically charged by the supply means.
 11. The flow cell accordingto claim 1 wherein the cannula is electrically charged by the supplymeans.
 12. The flow cell according to claim 1 wherein the cannula is thecounter electrode to the electrically charged cylinder.